Cell growth and proliferation Flashcards
What is cell proliferation specifically required for in adult life?
Repairing damaged tissue - wounds, replacement of skin
Adaptation to the environment - altitude - increased red blood cells numbers
Fighting infections - immune responses - antibody production, increased number of lymphocytes.
Learning - adult neurogenesis.
What is cell proliferation required for generally in adult life?
Tissue maintenance - turnover of cells in the haemopoietic (blood) system is particularly high.
Skin and gut cells are also replaced at a high rate.
Most tissues need to replace cells when they reach the end of their life.
What are terminally differentiated cells?
Mature cells which have lost the ability to differentiate.
What is homeostasis?
The maintenance of functional (differentiated) cells within tissues.
How are differentiated cells replaced?
Differentiated cells need to be replaced from precursors - stem cells.
What are stem cells?
Stem cells are responsible for re-seeding proliferating precursor cells.
These cells differentiate to replace dying cells to maintain the tissue.
Stem cells are present in small numbers in tissues.
What are the main types of stem cells?
Pluripotent / embryonic - have the ability to produce any type of differentiated cells.
Lineage committed stem cells - produce a restricted type of cell, in adults.
Stem cells amplify through division to form many precursor cells, then differentiate into terminally differentiated stem cells.
What is the most important property of stem cells?
Self-renewal.
Stem cells divide asymmetrically - unequally - gives rise to two types:
Stem cells and transit amplifying precursor cells.
Ensures stem cell population is maintained.
How does cell number control happen in the gut?
In the intestinal crypt in gut wall:
Stem cells reside at base of crypt then expand out from proliferation zone and become post-mitotic - don’t divide.
As they proliferate, epithelium moves up the crypt, there is a constant spread of cells up the crypt to the tip of villus, out of range of signals, then apoptosis occurs and cells die, and are replaced from below.
Occurs every 3-5 days.
What is the structure of the intestinal crypt in the gut wall?
Crypts - depressions in structure
Top of crypt - villi - extend into lumen of intestine - the absorbative epithelium.
see picture
Where are stem cells found?
In niches - they are in an environment where they can receive signals from surrounding tissue to control differentiation and maintain stem cell population.
What stimulates cell proliferation?
Mitogenic signals, from surrounding tissue.
What are the mitogenic signals for intestinal stem cell proliferation?
Mesenchymal cells produce mitogenic signals, strong in the base of the crypt, which communicate with the intestinal stem cells, and the transit amplifying cells, telling them to divide.
As it moves away from the mesenchymal cells, the levels decline.
As cells divide and move up the sheath, they escape the range of mitogenic signalling, stop proliferation, and differentiate into terminally differentiated cells.
What is cell proliferation?
Cell proliferation = cell growth and cell division
Growth = increase in cell size + cytoplasmic organelles, controlled by growth factors.
Division = chromosome duplication + mitosis + cytokinesis, controlled by mitogens.
What are the two phases of the cell cycle?
Cells proliferate via the cell cycle
Interphase - G1 (growth) + S (chromosomes duplicate) + G2 - the cell grows and nuclear DNA is duplicated
Mitosis and cytokinesis - M phase - the nucleus and cytoplasm divide to form two daughter cells.
What are Cdks?
Regulators of the cell cycle - cyclin-dependent kinases.
Catalytic subunit - Cdk - inactive unless bound to cyclin subunit.
Regulatory subunit - cyclin.
Cdks phosphorylate proteins that are important for specific cell cycle phases.
How do cyclin levels fluctuate during cell cycle phases?
Activated by specific cyclin subunits
Different cyclin-Cdk dimers regulate each cell cycle phase.
Ensures tight regulation of each phase - can lock differenent phases e.g. can cause a cell to stay in G1.
What are the types of Cdks and Cyclins?
G1-Cdk, has cyclin D, Cdk4 and Cdk6 partner.
G1/S-Cdk, cyclin E, Cdk 2 partner.
S-Cdk, cyclin A, Cdk2 partner.
M-Cdk, cyclin B, Cdk1 partner.
Which cyclin subunit is present in which phase of the cell cycle?
DEAB:
D - G1 (end of)
E - G1 to S
A - S
B - Mitosis
The levels fluctuate.
What are the essential steps during the cell cycle?
G1 - increase in cell size + duplicate cytoplasmic organelles
G1 checkpoint - overcome the restriction point
S - replicate the chromosome once, only
G2 - make sure the chromosomes are fully duplicated
M - Separate the duplicated chromosomes.
M - Cytokinesis - separate the daughter cells.
What is the restriction (R) point in G1?
A checkpoint through which cells can only progress if appropriately stimulated by mitogens.
Cells enter a quiescent phase (G0) when growth factors are limiting, cells may stay here for weeks or months.
Once through the R point, further mitogenic signalling is not required to complete the cell cycle.
How is cyclin D induced?
In G1, in the presence of growth factors, cells activate and expresses intermediate early genes - Myc, which encodes transcription factors .
Myc controls the expression of cyclin D - delayed response gene.
Cyclin D activates Cdk 4 and 6 to form active G1-Cdk.
What can G1-Cdk do?
Unphosphorylated pRb binds to the E2F transcription factor to repress cell cycle gene transcription.
G1-Cdk can then activate target proteins - pRB by phosphorylation, which enables progression through the R point.
What does G1/S-Cdk do?
Phosphorylated pRb releases E2F, targets genes cyclin E and A, which activates G1/S-Cdk.
G1/S-Cdk hyperphosphorylates pRB so it is completely inactivated in a feedback loop.
E2F activates transcription of genes required for chromosome duplication in S phase.
